FDA Approves Alimta as Second-Line Tx

FDA Approves Alimta as Second-Line Tx

ROCKVILLE, Maryland-
The FDA has granted accelerated
approval to Eli Lilly's Alimta
(pemetrexed for injection) for the
treatment of locally advanced or metastatic
non-small-cell lung cancer
(NSCLC) in previously treated patients.
The agent was approved earlier
in 2004 for use in combination with
cisplatin (Platinol) for the treatment
of malignant pleural mesothelioma
(see report on page 19).
The FDA accelerated approval is
based on Alimta's activity and favorable
safety profile as evidenced in a
phase III trial in the second-line setting
comparing Alimta with docetaxel
(Taxotere). In July, the study was the
basis for a unanimous recommendation
for accelerated approval by the
FDA's Oncologic Drugs Advisory
Committee (ODAC). A company
whose drug enters the market with
accelerated approval must conduct
postmarketing clinical trials to confirm
the agent's safety and efficacy.
Alimta disrupts folate-dependent
metabolic processes essential for a
tumor's rapid growth-specifically
three enzymes: thymidylate synthase,
dihydrofolate reductase, and glycinamide
ribonucleotide formyltransferase.
The antifolate drug is
converted to polyglutamate forms in
tumor cells, which results in a prolonged
drug action in malignan
cells. "Activity is seen across a wide
spectrum of scientific tumor models,"
Roy Herbst, MD, PhD, chief of thoracic
oncology, MD. Anderson Cancer
Center, told ODAC members at
the July meeting.
Pivotal Trial
Lilly's pivotal study, designated
JMEI, involved 571 patients in a randomized,
controlled, unblinded trial
of Alimta and docetaxel, the standard
second-line treatment, carried out at
135 sites in 23 countries (J Clin Oncol
22:1589-1597, 2004). Approximately
21% of the participants received
treatment in the United States. The
trial's primary endpoint was overall
survival.
Study enrollment began on March
20, 2001, and ended on February 6,
2002. Researchers randomized 283
patients to receive Alimta 500 mg/m2
intravenously on day 1 of each 21-day
cycle, plus 350 to 1,000 μg of oral
folic acid daily, 1,000 μg of vitamin
B12 every 9 weeks, and dexamethasone.
The remaining 288 participants
were assigned to receive 75 mg/m2
of docetaxel intravenously on day 1
of each 3-week cycle, plus dexamethasone.
Among the Alimta-treated patients,
85 (32%) crossed over to
docetaxel therapy after tumor progression,
a finding whose meaning became
a point of contention between
the sponsor and the FDA's reviewers
at the ODAC meeting.
The unblinding of the JMEI analysis
data sets occurred on January 30,
2003. According to both the sponsor
and the FDA review team, there was
no significant difference in survival,
(the primary endpoint) between the
two arms of the study, the primary
endpoint, nor in response, progressionfree
survival, or time to disease progression.
Among the patients actually
treated (264 with Alimta and 274 with
docetaxel), 9.1% of the Alimta group
and 8.8% of the docetaxel arm responded, and 45.8% of the Alimta patients
and 46.4% of the docetaxel
group showed stable disease.
"Notice the fact that over 50% of
the patients had either a major response
or stable disease in this trial,"
said Richard J. Gralla, MD, immediate
past president of the Multinational
Association of Supportive Care in
Cancer (MASCC), who spoke on behalf
of Lilly at the ODAC meeting.
Among the treated patients, researchers
found no statistically significant
difference in on-study deaths
between the two groups, 11.7% in the
Alimta group and 14.5% in the
docetaxel arm regardless of cause, or
in drug-related deaths, 1.1% vs 1.8%.
However, a significant difference was
seen in the percentage of drug-related
deaths among patients who suffered
one or more significant adverse
events, 10.2% in the Alimta arm, compared
with 23.9% in the docetaxel
group (P < .001).
JMEI researchers did find significant
differences favoring Alimta in
several grade 3-4 adverse events
among the treated patients. These included
neutropenia, 5.3% vs 40.2%
for the docetaxel group; febrile neutropenia,
1.9% vs 12.7%; and infection
with grade 3-4 neutropenia, 0.0%
≤ 5.8% (all P ≤ .001). Among
nonlaboratory grade 3-4 toxicities,
diarrhea occurred in 0.4% of the
Alimta group and 4.0% in the
docetaxel arm (P ≤ .006), and for all
grades of alopecia, the respective numbers
were 11.3% vs 42.4% (P ≤ .001).
"Because all the efficacy parameters
were equivalent, much of the clinical
benefit of Alimta relates to the
toxicity, and so the toxicity analysis
becomes important," said Paul A.
Bunn, Jr., MD, director, University of
Colorado Cancer Center, and a coprincipal
investigator, who presented
the JMEI efficacy data.
Issue of Noninferiority
ODAC members found themselves
grappling with the issues of whether
Alimta met FDA's criteria for a noninferior
drug and whether it had a more
favorable toxicity profile than
docetaxel.
FDA medical officer Martin H.
Cohen, MD, argued that Alimta failed
to meet the noninferiority test for two
reasons. First, the one small historical
study available (104 patients) for
docetaxel made it impossible for FDA
to precisely estimate the survival
effect of docetaxel in this setting. Second,
the 32% crossover of Alimta
patients to docetaxel after tumor progression
confounded the comparison
of survival between the two drugs, as
did the fact that only 139 Alimta patients
received no poststudy chemotherapy,
compared with 169 in the
docetaxel group. "The 30-patient difference
between the two treatment
arms might be important because patients
on both study arms who did
not receive poststudy chemotherapy
had shorter median survival," Dr.
Cohen said.
After discussion, ODAC members
voted on three questions put to them
by the FDA relating to Alimta. By a
vote of 13 to 0, the committee found
that Alimta had a more favorable toxicity
profile than docetaxel. It also voted
13 to 0 that Alimta's toxicity profile
and the supporting efficacy data
showing noninferiority outweighed
the uncertainty about a possible loss
of survival effect that might result
from Alimta. FDA officials described
this decision as a vote recommending
accelerated approval for Alimta. Finally,
ODAC members voted 8 to 5
that the drug did not warrant full
approval.

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